As new treatment modalities for ophthalmic diseases become available, the number of intravitreous injections administered is expected to increase dramatically. For example, intravitreous injection of the vascular endothelial growth factor (VEGF) inhibitor, Macugen® ((OSI) Eyetech, Inc. NY, N.Y.), has become available for the treatment of age-related macular degeneration. Macugen is currently delivered via intravitreous injection every six weeks.
Advantages of intravitreous injection of medicines and diagnostics include the achievement of maximum vitreous concentrations while minimizing toxicity attributed to systemic administration. While these advantages are becoming widely appreciated, the ophthalmology community turns its focus to various complications potentially associated with intravitreous injection. Risks of intravitreous injection, some vision threatening, include endophthalmitis, retinal detachment, iritis/uveitis, inflammation, intraocular hemorrhage, ocular hypertension, hypotony, pneumatic retinopexy, and cataract (R. D. Jager et al., Retina 24:676-698, 2004 and C. N. Ta, Retina, 24:699-705, 2004). Methods of minimizing such risks include developing sustained release ophthalmic formulations to minimize the number of intraocular injections.
Ophthalmic inserts are solid devices intended to be placed in the conjunctival sac and to deliver the drug at a comparatively slow rate. One such device is Ocusert® (Alza Corporation, Mountain View, Calif.), which is a diffusion unit consisting of a drug reservoir enclosed by two release-controlling membranes made of a copolymer. M. F. Saettone provides a review of continued endeavors devoted to ocular delivery. (“Progress and Problems in Ophthalmic Drug Delivery”, Business Briefing: Pharmatech, Future Drug Delivery, 2002, 167-171). Other implant strategies have been developed for small, highly potent, lipophilic therapeutics. (G. A. Peyman, et al., “Delivery Systems for Intraocular Routes” Advanced Drug Delivery Reviews, (1995) 16, 107.) While these implants are effective for the delivery of steroids, the small size of the implants preclude long-term (>30 days) delivery of large, water-soluble compounds. In addition, formulation conditions for most polymeric delivery systems are not compatible with proteins, antibodies, and other biotherapeutics (S. P. Schwendeman et al., “Peptide, protein, and vaccine delivery from implantable polymeric systems: Progress and challenges” Controlled Drug Delivery, (1997) 229).
Encapsulation of pharmaceuticals in biocompatible, biodegradable polymer microparticles can prolong the maintenance of therapeutic drug levels relative to administration of the drug itself. Sustained release may be extended up to several months depending on the formulation and the active molecule encapsulated. In order to prolong the existence at the target site, the drug may be formulated within a matrix into a slow release formulation (see, for example, Langer (1998) Nature, 392, Supplement, 5-10). Following administration, drug then is released via diffusion out of, or via erosion of the matrix. Encapsulation within biocompatible, biodegradable polyesters, for example, copolymers of lactide and glycolide, has been utilized to deliver small molecule therapeutics ranging from insoluble steroids to small peptides. Presently, there are over a dozen lactide/glycolide polymer formulations in the marketplace, the majority of which are in the form of microparticles (T. Tice, “Delivery with Depot Formulations” Drug Delivery Technology, (2004) 4(1)).
Several techniques for the production of lactide/glycolide polymer microparticles containing biological or chemical agents by an emulsion-based manufacturing technique have been reported. In general, the methods include preparation of a first phase consisting of an organic solvent, a polymer and a biological or chemical agent dissolved or dispersed in the first solvent. A second phase comprises water and a stabilizer and, optionally, the first solvent. The first and second phases are emulsified and, after an emulsion is formed, the first solvent is removed from the emulsion, producing hardened microparticles.
Microparticles can also be produced using a water-in-oil-in-water (w/o/w) process. W/o/w emulsions can be considered as an aqueous emulsion of oil droplets which in turn contain a dispersed aqueous phase. Examples of w/o/w emulsion processes are described in U.S. Pat. Nos. 4,954,298; 5,330,767; 5,851,451 and 5,902,834, each of which are hereby incorporated herein by reference in their entirety. The w/o/w process described above is typically used for water-soluble molecules.
In addition, U.S. Pat. No. 6,706,289, hereby incorporated in its entirety by reference, discloses controlled release formulations of biologically active molecules that are coupled to hydrophilic polymers such as polyethylene glycol and methods of their production. The formulations are based on solid microparticles formed of the combination of biodegradable, synthetic polymers such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and copolymers thereof. PCT WO 03/092665, hereby incorporated in its entirety by reference, discloses microsphere formulations for the sustained delivery of an aptamer, for example, an anti-Vascular Endothelial Growth Factor aptamer, to a pre-selected locus in a mammal. Such formulations are further disclosed in K. G. Carrasquillo et al., “Controlled Delivery of the Anti-VEGF Aptamer EYE001 with Poly(lactic-co-glycolic) Acid Microspheres,” I.O.V.S. (2003) 44(1), 290.
Patient acceptance and safety are key issues that will play a role in which treatments are used. Frequent intraocular injections may not be favorable because they cause patient discomfort and sometimes fear, while risking permanent tissue damage. Therefore there remains a need for developing sustained release ophthalmic formulations to minimize the number of intraocular injections.